Senile osteoporosis increasingly affects the aging population of the United States and, along with post- menopausal osteoporosis, impacts more than 20 million women and men with an annual estimated cost of 14 billion dollars. Increased skeletal loading and exercise may be helpful in preventing senile osteoporosis, but clinical studies have not demonstrated a consistent benefit, perhaps because a reduction in the number of bone marrow osteoprogenitor cell renders the osteoporotic skeleton unable to respond to loading. Our overall goal is to test the hypothesis that the vigor of the osteogenic response following increased mechanical loading depends in part on the number of bone marrow osteoprogenitor cells. To address this question we will utilize a unique animal model of senile osteoporosis, the senescene accelerated mouse (SAM). For Aim 1 we will use femurs and tibias from control SAMRI and osteoporotic SAMP6 mice at three ages to quantify mechanical properties ex vivo (using four-point bending and nanoindentation) and marrow osteogenic potential in vitro (using bone marrow cell cultures). We will determine whether or not to relative differences in mechanical properties between SAMR1 and SAMP6 correlate with differences in marrow osteogenesis in vitro. For Aim 2 we will develop validated computed tomography- based finite element models of tibias from SAM mice and use them to predict strain distributions in the cortical diaphysis during in vivo four-point bending. These models will allow us to deliver prescribed strain magnitudes to the endosteal bone surface and to establish conditions for subsequent in vivo experiments. Finally, for Aim 3 we will cyclically load the tibias of SAM mice in vivo at three prescribed strain magnitudes and evaluate the skeletal response using peripheral computed tomography and dynamic histomorphometry and the bone marrow response using in vitro cell culture. We will determine whether or not loading increases the number of osteoprogenitor cells in the bone marrow and whether or not the magnitude of the osteogenic response correlates with changes in the bone marrow and is proportional to the number of osteoprogenitor cells. Finding from these studies will represent an important first step toward our long-term goal of determining the role of marrow osteoprogenitor cells in maintaining skeletal integrity and in mediating the response of bone to mechanical loading.